OXYGEN CONSUMPTION AND THERMOREGULATION
Metabolic Rate
Requirements for determining the basal metabolic rate include a 12-h fast and full
relaxation. These conditions are nearly impossible to fulfill in the neonate, however, the
maximum increase in energy metabolism is less than 10% after a feeding. Therefore,
measurements in neonates are usually made in the fed state over a 5-10 minute period, although a
1-hour period is preferred to ensure that the minimum oxygen uptake has been reached at some
point during the recording period. Measurements should be made in a thermoneutral
environment and the neonate may be sleeping during these measurements. The minimum
metabolic rate measured in this way is called the standard metabolic rate (SMR).
The SMR, although proportional to body size, is not directly proportional. Smaller
animals will have a higher metabolic rate per unit of body mass; this is described by the law of
metabolic reduction (SMR = 3.29 x W0.75). Although this is useful for predicting differences in
metabolic rates between species, it has limitations when comparing individuals within a species.
Sex, body shape and body composition all affect metabolic rate, however, age is the biggest
factor preventing a single equation from being useful within a species.
The SMR is lower than predicted in newborns, with a 3-kg human having a lower SMR
than a 3-kg mature rabbit. The most appropriate exponent during this period is 1, meaning that
the SMR per unit of body mass is nearly independent of weight, whereas a decease would
normally be expected. However, from 5-20 kg, human SMR is greater than in mature animals of
the same weight range. Above 20 kg, SMR finally conforms to the law of metabolic reduction.
Values for the first few hours of life in infants are within the range of 4.6 to 5 ml/kgmin.
The postnatal increase appears to be species-dependent; it takes a matter of days in primates and
laboratory animals and a matter of hours in the lamb. The more rapid increase in SMR does not
occur in fasted lambs, however, suggesting that the onset of digestion and absorptive processes
may account for much of this increase.
Much of the “violation” of the law of metabolic reduction in neonates may be related to
differences in extracellular fluid content of neonates. Extracellular fluid may account for 44% of
a 4000-g full-term neonate and up to 58% in premature infants (1000-g) while only accounting
for 16% of an adult human. Since ECF is not metabolically active, it may be more accurate to
refer to active tissue mass, or to active tissue mass plus 16% to bring values to an adult basis.
Although this manipulation does bring neonatal values back into line with the law of metabolic
reduction, deviations seen at older ages are not so easily explained. The higher rates seen at
these ages may be a function of higher thyroid function at these ages and especially as a function
of brown fat metabolism, which can account for as much as 30% of the SMR at this age.
Heat Production
Thermoregulation in homeothermic organisms, especially animals that have a small
surface:volume ratio and an effective insulating layer of subcutaneous fat or hair, is primarily
concerned with dissipating metabolic heat. In contrast, small animals or animals without an
effective insulating layer need effective mechanisms for supplemental heat production to ensure
survival.
The thermoneutral zone in neonates is defined as the range of ambient temperature within
which metabolic rate is at a minimum, and within which temperature regulation is achieved by
nonevaporative physical processes alone. In the unclothed resting adult, the lower limit of the
thermoneutral zone is 26-28 C, while in newborns it is 32-34 C. Environmental temperature
conditions that require no thermoregulatory effort in the adult may easily overtax the metabolic
thermoregulatory capabilities of the newborn infant. In very small premature infants, the lower
limit of the thermoneutral zone may be as high as 35 C.
There are three principal modes of heat production in response to cold stress: 1) voluntary
muscle activity, 2) involuntary tonic or rhythmic muscle activity, which may be low-intensity and
not visible, or higher intensity visible shivering, and 3) non-shivering thermogenesis. In most
mature mammals, shivering is quantitatively the most important involuntary mechanism for
thermoregulation and non-shivering thermogenesis develops only after long-term cold exposure.
In neonates, non-shivering thermogenesis is a quantitatively important and effective mechanism
for heat production. The elicitation of non-shivering thermogenesis is mediated by the
sympathetic nervous system and can be blocked by -receptor antagonists such as propranolol.
Non-shivering thermogenesis is the preferred mode of heat production in neonates and will
suppress shivering.
Metabolically active brown fat is a major site of thermogenesis, and comprises
approximately 1 per cent of the human adult body mass, while the metabolically inactive white
fat functions primarily as fat storage. In neonates, it may comprise as much as 5 to 7% of body
weight (except in the pig, which completely lacks brown fat). Brown fat cells contain an
abundance of sympathetic nerve fibers which actually maintain synaptic contact with the cell
membrane. These release norepinephrine which triggers thermogenesis and activates lipase. The
cells have a centrally located nucleus surrounded by multiple fat lobules surrounded by
mitochondria. The specialized function depends on a 32 KDa protein in the mitochondrial inner
membrane called the “uncoupling protein” or thermogenin. The role for this protein is to shortcircuit the electrochemical gradient generated by the respiratory chain.
As a general rule, except in brown adipose tissue, coupling between substrate oxidation
and ADP phosphorylation in the mitochondria is due to the development of an electrochemical
gradient on either side of the mitochondrial matrix. This gradient cannot be discharged except at
specific sites (F1-ATPase) where ATP-synthase is located. This controlled discharge of this
gradient generates the energy used for ATP production. Thus electron transfer from substrates to
oxygen produces stochiometric amounts of ATP during coupled oxidative phosphorylation. By
contrast, in brown adipose tissue mitochondria, the uncoupling protein allows discharge of this
gradient without generation of ATP. The energy generated by uncoupling oxidative
phosphorylation is simply released as heat.
Postnatal development of respiratory enzymes and the uncoupling protein (UCP) in
brown adipose tissue occurs during the first few hours after birth and is accelerated and enhanced
by cold stress. The synthesis of the uncoupling protein is under noradrenergic control, and the
UCP gene is acutely regulated at the level of transcription after activation of the plasma
membrane -adrenoreceptors of the brown adipocyte. Therefore, the rapid increase in UCP
found in brown adipose tissue mitochondria of cold-stressed neonates is most likely due to a
rapid increase in the rates of transcription of the UCP gene.
Blood flow through intrascapular deposits of brown fat in the newborn rabbit increase
from approximately 90 ml/100 gmin to over 700 ml/100 gmin during cold exposure, accounting
for up to 25% of cardiac output. Brown adipose tissue can provide up to 2/3 of the total heat
provided from non-shivering thermogenesis under conditions of maximal stimulation.
The existence of extensive brown fat deposits at birth may be a compensatory mechanism
for the smaller body size since thermoregulatory efficiency of non-shivering thermogenesis is
greater than that of shivering. In precocial newborns, the extent of non-shivering thermogenesis
is greatest at birth and vanishes within a few weeks. Cold exposure during this period prevents
the disappearance of non-shivering thermogenesis, however, with increasing age, the extent to
which it can be maintained (or evoked) is decreased. Altricial neonates have gradual increases in
non-shivering through the first few weeks of life.
Cold-induced heat production maintains body temperature as long as heat loss does not
exceed the capability for heat production. As soon as this capability is exceeded, body
temperature begins to decrease. Both cold-induced heat production and basal heat production
will decrease as body temperature falls, with oxygen uptake decreasing by a factor of 2- to 3-fold
per 10 C change in body temperature. The thermoregulatory drive as generated in the
thermointegrative area of the CNS is reduced with increasing hypothermia.
Neonates of all species, except the ground squirrel and the golden hamster, are capable of
a cold-induced metabolic response immediately after birth, however, during the first few hours or
days of life, this increase is reduced. The lamb is the only species of those studied that had a
response that was actually greater than that predicted to be maximal; lambs were also the only
precocial species studied and this data would be consistent with the changes in non-shivering
thermogenesis described earlier.